Active vitamins D3 such as 1α-hydroxycholecalciferol (1α-hydroxyvitamin D3) and 1α,25-dihydroxycholecalciferol (1α,25-dihydroxyvitamin D3) have the effects of promoting calcium absorption in the small intestine, controlling bone metabolism in the bone, controlling parathyroid hormone production in the parathyroid, inducing differentiation in tumor cells, suppressing immune response, etc. Therefore, they are considered to be effective for treating renal failure associated with lowered calcium absorption, osteoporosis caused by abnormal bone metabolism, hyperparathyroidism, malignant tumors, autoimmune diseases and the like.
However, all these compounds are unstable to light and heat and to be put to use in medical applications, this problem is required to be overcome. Formulations containing active vitamins D3 as active ingredients are used at varying active ingredient levels because the dose varies with the disease or condition. Thus, it is important that the active ingredient level in each formulation can be readily discriminated in order to prevent medical fault.
It is also important to ensure content uniformity of active vitamins D3 in formulations because they are effective at a very low dose such as several tens of micrograms.
Known formulations of active vitamins D3 include a soft capsule formulation of an active vitamin D3 wherein an oily solution of the active vitamin D3 is encapsulated with a capsule shell containing 1.0% by weight or less of a UV absorber having a light transmittance of 10% or less at a wavelength of 310 mμ in 0.01% by weight aqueous solutions and having absorption in the visible range (JPA No. 84023/1979). Other soft capsule formulations for stabilizing light-unstable compounds so far reported include a soft capsule formulation wherein a dye absorbing a specific wavelength of light and an opacifier are homogeneously dispersed in a gelatin shell (JPA No. 28621/1973); a soft capsule formulation wherein Food Color Yellow No. 5 is homogeneously dispersed in a soft capsule shell to stabilize light-unstable compounds in said soft capsule shell (JPA No. 22645/1980); a soft capsule formulation wherein an edible tar-based dye such as Food color Yellow No. 4 is dispersed in a capsule shell (JPA No. 13511/1983), etc. However, recent scientific research has shown that a UV absorber having absorption in the visible range, and dyes used in these disclosed techniques, which are tar-based synthetic dyes or synthetic colorants, have doubtful safety. Moreover, these formulations are inconvenient for international distribution because the permitted classes of dyes vary between countries.
On the other hand, a method for stabilizing active vitamins D3 without using a tar-based synthetic dye or a synthetic colorant is known, such as a soft capsule formulation using a capsule shell containing a natural dye such as cocoa dye, apigenin, carminic acid, carminic acid lake, laccaic acid or shikonin (JPA No. 53923/1987). However, it is difficult to always maintain a uniform color tone with these natural dyes, which vary in color tone with the batch lot, and also tend to be unstable.
A method for stabilizing active vitamins D3 by using an inorganic compound is also known, such as a soft capsule formulation using a capsule shell containing fine particles of titanium oxide wherein at least 85% of titanium oxide has a particle diameter of 0.1 μm or less (JPA No. 166824/1988). However, titanium oxide has a white color tone, which is insufficient for discriminating active ingredient levels and requires some additional colorants to enable better discrimination.
Known colorants other than the above tar-based dyes, synthetic colorants and natural dyes include iron oxide, caramel and the like. A soft capsule formulation using iron oxide is described in JPA No. 84023/1979, which discloses a soft capsule formulation of an active vitamin D3 encapsulated with a shell containing yellow iron oxide and red iron oxide, but it is reported to be insufficient in stability to heat. A method for preventing destabilization of active ingredients due to direct contact of the active ingredients with red iron oxide (diiron trioxide) in soft capsule shells is reported by JPA No. 157911/1989, which discloses a light-screening capsule formulation wherein microencapsulated red iron oxide is dispersed in a shell to prevent direct contact of red iron oxide with the drug in the capsule, but this method is not a practical means of production since it requires complex operations such as the preparation of microcapsules containing red iron oxide. A gelatin shell colored with caramel (JPA No. 127448/1980) is also known, but its effect on the stability of active vitamins D3 to light or heat is unknown.